An obese and hypertensive 63-year-old Caucasian woman presented with persistent and progressively worsening exertional dyspnea, occasionally accompanied by anginal chest pain as well as dysphonia, hoarseness, dysphagia, complaints of lower extremity weakness, and documented mild chronic L5-S1 denervation. Work-up revealed moderate obstructive ventilatory defect, borderline restrictive defect, and variable extrathoracic obstruction. Weakness and progressively poor quality of sleep characterized by sleep-disordered breathing, increased daytime somnolence, fatigue upon waking and increased snoring were added to her initial complaints. A sleep study established the diagnosis of severe obstructive sleep apnea. Treatment with continuous positive airway pressure (CPAP) produced significant improvement in her energy levels, more restful sleep and less fatigue, but her dyspnea worsened. A new cycle of cardiac and respiratory evaluation was positive for mild pulmonary hypertension and negative for myocardial ischemia and pulmonary fibrosis. Shortly after these last assessments, and two to three years after onset of symptoms, the patient died suddenly in her sleep.

NEUROPATHOLOGY

The general autopsy revealed emphysema and cardiomegaly with no coronary atherosclerosis and no acute pulmonary or cardiac disease to explain sudden death. Gross examination of the brain showed only a slightly flattened left inferior olive. The spinal cord appeared normal. Microscopic examination confirmed mild, patchy neuronal loss in the left olive. Neuronal loss was prominent in the anterior horns of the spinal cord, with relatively few remaining neurons (arrows, Figure 1a). There was no neuronal loss in substantia nigra, striatum, cerebellum, or basis pontis, with only modest reactive astrocytosis and rare neuronal ballooning in the pons, medulla and spinal cord. The corticospinal tracts were unremarkable.

Immunohistochemical staining for alpha-synuclein highlighted intracytoplasmic inclusions in the midbrain, pons, medulla, cerebellum and spinal cord. The inclusions were most numerous in the medulla (Figure 1b) and the gray matter of the spinal cord (Figure 1c). The inclusions also stained for ubiquitin but not tau. There were no ubiquitin-positive inclusions in motor neurons to suggest amyotrophic lateral sclerosis. The diaphragm showed scattered groups of atrophic skeletal muscle fibers (Figure 1d). What is your diagnosis?